tbuckley/cabot-search huggingface dataset:
P10.09.B Retroelement expression in glioma tumors exhibits subtype specific patterns
Authors: J Rodriguez Almaraz, G Guerra, G Wendt, S Chang, S S Francis
Journal: Neuro-Oncology (2022)

Abstract Background There are ~3 million transposable elements in the human genome constituting about 42% of all basepairs. Retroelements (REs) are ~90% of the transposable elements present in the human genome. Active REs are considered highly mutagenic and have been implicated in multiple steps of cancer development and progression, as well as in neurologic diseases. RE activity has functional effects on the genome, including the maintenance of centromere and telomere integrity, and deleterious gene expression. Previous studies have shown that certain families of RE (HERVK, L1, Alu) are expressed in gliomas, however, their specific role as arbitrators of oncogenesis or promoters of the innate anti-tumor immune response remains uncertain. Moreover, it has been shown that a soluble form of PD-L1 (sPD-L1) that blocks its inhibitory activity is produced by exaptation of an intronic endogenous retroelement (LINE-2A) in the gene encoding PD-L1, highlighting the importance of REs as potential therapeutic targets. In this analysis we aim to identify the unique patterns of RE expression across major subtypes of glioma. Material and Methods We conducted a differential expression analysis of 49 RE families using RNA-seq data measured in glioma tumors from The Cancer Genome Atlas (TCGA). RE counts were produced using the software REDiscoverTE. Pairwise comparisons between glioma subtypes (defined by WHO2021) were done using in 625 tumor samples adjusting for age, sex and race. Results 10 of the 49 considered RE families exhibited significantly different (false discovery rate, FDR, &amp;lt;0.05) expression in at least one glioma subtype. Alu(Fold change, FC=1.5), RNA(FC=11.3), PiggyBac(FC=1.6), rRNA(FC=5.23) and Dong-R4(FC=1.8) were overexpressed in IDH-wildtype glioblastoma while Gypsy(FC=0.4) and CRP1(FC=0.26) were decreased in expression. scRNA (FC=2.7) were overexpressed in IDH-mutant oligodendroglioma compared to glioblastoma while Dong-R4 (FC = 0.53) showed decreased expression. LTR (FC=2.02) and tRNA-Deu (FC=1.46), showed increased expression in IDH-wildtype diffuse astrocytomas compared to IDH-mutant, 1p/19q-codeleted oligodendrogliomas while Gypsy (FC =0.41) showed decreased expression. Conclusion We have shown that expression of certain RE families within gliomas have subtype-specific patterns. While it is well established that RE expression is dysregulated in cancer, our analysis is the first at exploring a wide range of retroelements in the context of glioma by subtype. Given the important role of REs in transcriptional control, genomic instability, chromosomal rearrangements, and oncogenic activation, the identification of individual families and specific REs in glioma holds an intrinsic value to potential biomarkers and immunotherapy targets.
P09.02.B Engaging Parents in Neuropsychological Rehabilitation for Childhood Cancer Survivors: The I’M aware: Patients And Carers Together (ImPACT) Program
Authors: L M Wu, L T Henriksen, C R Buskbjerg, Y Lassen-Ramshad, R Zachariae, L Evald, H Hasle, A Amidi
Journal: Neuro-Oncology (2022)

Abstract Background Cognitive impairment is the most common late effect in childhood cancer survivors (CCS). A third are likely to experience impairments in skills such as attention, processing speed, memory, and executive function. Neurobehavioral impairments are also observed in CCS (e.g., apathy) and may underlie cognitive impairment. Although these problems can impair quality of life, scholastic achievement and long-term socioeconomic outcomes, there is a dearth of research on interventions to treat cognitive impairment in CCS. Cognitive rehabilitation studies in CCS have focused primarily on computerized cognitive training and meta-cognitive strategy training, but with limited effects and poor study designs. They have lacked four key elements: 1) transfer of learning to real-world functional outcomes; 2) awareness training to enhance compensatory strategy use, particularly since CCS may experience neurological unawareness preventing the optimal application of strategies; 3) inclusion of parents that could enhance transfer of learning to the home; and 4) recognition of the inter-related nature of cognitive, neurobehavioral, and psychological functions. A novel, context-sensitive neuropsychological rehabilitation program has been developed for CSS to address these missing elements - the “I’M aware: Patients and Carers Together (ImPACT)” program - based on an evidenced-based approach pioneered at NYU Hospital in the US. In this protocol, the feasibility, acceptability, and preliminary efficacy of the ImPACT program (8 x 1 hour sessions) will be evaluated. Material and Methods Phase One will consist of semi-structured interviews with 5 to 10 CCS and their parents in order to review and refine procedures for the ImPACT program. In Phase Two, twenty participants will be randomized to a wait-list control (WLC) or intervention group. WLCs will not receive the intervention immediately, but will serve as the control comparison group. Measures of self- and parent-reported cognition, neurobehavioral function, and global function will be administered pre- and post- intervention, and 9 weeks later (or equivalent time points for WLCs). Results Results of this project will provide vital data in support of a future large-scale trial. Conclusion Findings could have implications for the management of cognitive and neurobehavioral impairment in CCS that could transform the nature of services provided to CCS. The program can be delivered remotely or in-person and harnesses existing supports in the child’s life to promote real-world functioning.
P12.15.B Astrocyte immunometabolic regulation of the glioblastoma microenvironment drives tumor pathogenicity
Authors: R Perelroizen, B Philosof, N Budick-Harmelin, T Chernobylsky, K Rotem, A Ron, D Shimon, A Tessler, O Adir, A Gaoni-Yogev, T Meyer, A Madi, E Ruppin, L Mayo
Journal: Neuro-Oncology (2022)

Abstract Background Malignant brain tumors are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumors, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumor associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain's metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Material and Methods Immunocompetent mice were implanted with murine glioma cell lines and the role of astrocyte in the tumor pathogenicity was analyzed, and further investigated using in-vitro co-cultures. Results Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumor-associated astrocyte translatome, revealed that astrocytes initiate transcriptional programs that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumor-associated macrophages and promotes a pro-tumorigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumor progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumor microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. Conclusion These findings suggest that targeting astrocyte immunometabolic signaling may help treat this uniformly lethal brain tumor.
P02.07.B Patient-derived glioblastoma organoids: Elucidating the mechanisms of glioblastoma therapeutic resistance in the context of tumor microenvironment
Authors: A Habič, B Majc, A Porčnik, R Bošnjak, J Mlakar, T Lah Turnšek, B Breznik, M Novak
Journal: Neuro-Oncology (2022)

Abstract Background Intratumoral heterogeneity plays an important role in glioblastoma (GB) resistance to standard therapy consisting of irradiation and chemotherapy with temozolomide (TMZ). However, classical in vitro GB models fail to represent the complex cellular composition of tumors in vivo, which hinders relevant examination of GB therapeutic response. To overcome these limitations, we studied the effects of irradiation and TMZ in a novel patient-derived organoid model. Material and Methods We established a patient-derived GB organoid model by a protocol recently published by Jacob et al. Original tumor tissue and tissue-derived organoids were compared by immunofluorescence staining of selected cell type markers and qPCR analysis of expression levels of a panel of selected target genes, including 15 genes defining GB subtypes. To analyze GB therapeutic response, organoids from 11 patients were exposed to a single dose of irradiation (10 Gy), one-week treatment with TMZ (50 µM) or their combination. The effects of therapy were assessed by viability and invasion assays. Expression levels of a number of genes related to GB subtypes, epithelial-mesenchymal transition, stemness, DNA damage responses, cell cycle, cytokines, and cell markers of the tumor microenvironment (TME) were compared between treated organoids and untreated controls. In addition, the heterogeneity of the TME and its responses to treatment were investigated by spatially resolved transcriptomics with in situ sequencing (ISS) methodology. Results Organoids recapitulate inter-patient variability and reflect the cellular composition and gene expression levels of the tumor tissue from which they were derived. GB stem cells and differentiated cancer cells are present in organoids along with various cells of the TME, e.g., macrophages and microglia, lymphocytes, and endothelial cells. Irradiation and TMZ showed no significant effects on organoid viability and invasion. However, some target genes were differentially expressed in the treated organoids, such as E3 ubiquitin-protein ligase MDM2 and cyclin-dependent kinase inhibitor 1A (CDKN1A). To our knowledge, we are the first to apply spatially resolved transcriptomics (ISS) to formalin-fixed, paraffin-embedded sections of (un)treated GB organoids. Our results elucidate the role of the TME in GB therapeutic response and shed light on potential mechanism underlying GB therapy resistance. Conclusion Patient-derived GB organoids recapitulate the key characteristics and complex composition of patient’s tumor tissue, providing a valuable platform for studies of GB therapeutic response and resistance.
P17.04.B Combination of Trofosfamide and Etoposide in Recurrent Glioma
Authors: T Schmidt, S Agkatsev, J Feldheim, C Oster, T Blau, U Sure, K Keyvani, C Kleinschnitz, M Stuschke, K Hermann, C Deuschl, B Scheffler, S Kebir, M Glas, L Lazaridis
Journal: Neuro-Oncology (2022)

Abstract Background Disease relapse almost inevitably occurs in patients with adult-type diffuse glioma. Standard of care treatment options at tumor relapse are still not well defined. Frequently used drugs for adult-type diffuse glioma recurrence include lomustine (CCNU) and bevacizumab. Few studies indicate that the combination of trofosfamide/etoposide, given their high lipid solubility with good blood-brain barrier penetrance, may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide/etoposide treatment at disease recurrence of patients with adult-type diffuse glioma. Material and Methods We collected clinicopathological data from adult patients with adult-type diffuse glioma treated with the combination of trofosfamide/etoposide at the Division of Clinical Neurooncology at the University Hospital Essen. Only those patients were considered eligible who received trofosfamide/etoposide treatment for more than four weeks (one course). Trofosfamide (100mg/m2/day) and Etoposide (25mg/m2/day) was administered orally in a “one week on, one week off” scheme. A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors (number of previous treatments, MGMT promoter methylation, IDH mutation status, KPS, age, extent of resection) served as control. We collected toxicity data as it pertained to CTCAE (Common Terminology Criteria for Adverse Events, version 5.0) and survival data to explore putative efficacy. Results A total of 33 patients were eligible for this analysis. In the IDH wild-type glioblastoma (n=18) subgroup, median progression-free survival (3.8 months versus 2.9 months, HR: 2.09, 95% CI: 1.010-4.312, p=0.0227; PFS-6: 39% versus 6%) and median overall survival (10.4 months versus 5.7 months, HR: 3.05, 95% CI: 1.393-6.655, p=0.0008) were significantly prolonged as compared to the control cohort. In a multivariable Cox regression analysis, treatment with trofosfamide/etoposide emerged as statistically significant prognostic marker regarding progression-free survival and overall survival. We observed high-grade adverse events (CTCAE grade≥III ) in 21 (64%) of all recurrent glioma patients with hematotoxicity comprising most adverse events (n=18, 86%). Lymphopenia was by far the most observed hematotoxic adverse event (n=13, 62%). Among non-hematologic high-grade adverse events was transaminase elevation (n=3, 14%). Conclusion This study provides first indication that the combination of trofosfamide/etoposide is safe in patients with adult-type diffuse gliomas and may be associated with prolonged survival in adult patients with recurrent IDH wildtype glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.
P17.18.B Augmentative craniotomy in recurrent glioblastoma. Preliminary clinical and radiological outcomes
Authors: U A Arcidiacono, L Berra, A Serraino, G Cedrone, E Venditti, D Armocida, A Quinzi, F Brunetto, L D'Angelo, V Di Norcia, A Frati, P Familiari, A Santoro
Journal: Neuro-Oncology (2022)

Abstract Background The compression of peritumoral healthy tissue in brain tumor patients is considered a major cause of life-threatening neurologic symptoms. This condition is associated with an increase in intracranial pressure. The literature reports that GBM has a mass effect in 72% of autoptic brains of patients who died of brain tumor, with herniation in 50% of all cases. Material and methods We present a preliminary clinical series on 5 cases. The patients are chosen based on criteria of recurrent glioblastoma without the possibility of a gross total resection with a recurrence after STUPP protocol. The surgeries include cytoreduction and augmentative craniotomy. The aim is to increase the intracranial volume and reduce the intracranial pressure in evolving glioblastoma. Clinical and radiological follow-up considers different objective scales and contrast enhancement MRI performed every 3 months. We evaluate KPS, survival rate, complication rate, quality of life using QOL-BN20 and neuropsychological assessment. Results The 12 months of follow-up shows a mean survival rate of 9 months after the surgery. This procedure has no negative impact on the survival rate, complication rate, and quality of life reduction. The neuropsychological evaluation does not show an impact on self-perception of aesthetic appearance. The surgery does not show surgical wound complications. The mean operative time was 225 minutes and was comparable with standard recurrence glioblastoma procedure. Conclusion This work has the main limitation of being preliminary results on small population. However, these results show encouraging outcomes and could be an innovative and salvage therapy for recurrent and incurable glioblastoma. Further follow-up and study must be performed.
P03.08.B Proton Therapy and recurrent Lower Grade Glioma: clinical and radiological aspects, intraoperative findings and histo-pathological features
Authors: M Conti Nibali, M Rossi, T Sciortino, L Gay, E Lopci, B Fernandes, R Rudà, L Bello
Journal: Neuro-Oncology (2022)

Abstract Background Radiation therapy (RT) plays a central role in management of central nervous system disease, in particular in the multimodality management of low(er) and high-grade CNS gliomas. New strategy that involved Proton Therapy (PT) have been experienced in the last years. No data are available about re-surgery of lesion irradiated with protons. Material and Methods We reviewed our single Unit experience of re-surgery of Lower-Grade Glioma patients that received, in their neuro-oncological history, a treatment with PT. We collect clinical data, intra-operative findings, histopathological features and oncological and clinical outcome after surgery. Results We collected three cases of young with an IDH1-mutated tumor that underwent to Proton Therapy (PT). In two cases PT was performed due to progression of disease, in one case as adjuvant therapy after first surgical treatment. In all cases we performed surgery within three years after PT. All patients complained drug resistant epilepsy after PT with symptom relief after surgery and one patient complained a spine fracture due to corticosteroids intake to control radionecrosis’s symptoms after PT. In the pre-operative work-up all patient performed a 11-C-Methionin PET scan that revealed an increase of tracer uptake in the suspected area of tumor progression. In one case advanced MRI protocol with PWI was performed to further distinguish and sample area of pseudoprogression and tumor progression. In two patients area of gliosis and necrosis was find at the histological examination. Conclusion Our experience, although limited to three case, provided a clinical and radiological example of the small cohort of patients that performed surgery after a Prothon Radiotherapy. Clinical presentation was heterogenous except a poor seizure control. Despite time elapsed since PT, areas of radionecrosis were found in the histopathological samples of 2/3 of patients. Moreover, we need to collect more data to draw a complete picture in this complex field.
P11.26.A STAT3 expression in brain metastases from breast cancer: correlations with different molecular subtypes and clinical outcome
Authors: A Pellerino, F Bruno, F Mo, L Bertero, E Bellini, A Beano, F Montemurro, M Valiente, R Rudà, R Soffietti
Journal: Neuro-Oncology (2022)

Abstract Background STAT3 expression in peritumoral reactive astrocytes (RA) of brain metastases (BM) may favor a pro-metastatic environment. The aim of the study was to evaluate in a retrospective cohort of surgically resected BM from breast cancer (BC) the expression of pSTAT3 in RA of peritumoral tissue of BM, identify different patterns of expression according to molecular subtypes, and correlate with intracranial progression-free survival (i-PFS). Material and Methods Patients with histologically proven BM diagnosis from BC were identified from the biobank of Pathology Unit of University of Turin and Spanish national BrM network (RENACER). pSTAT3 expression was evaluated and scored in RA of peritumoral tissue using GFAP and STAT3 immunohistochemistry, according to Priego et al. (Nat Med 2018). Data on histological diagnosis, molecular subtypes, and i-PFS were retrieved by chart review. Intracranial progression was defined based on MRI reports. Results Eighty-five BM specimens from BC of 85 female patients with a median age of 54 years (range 30-81 years) were available for analysis. Immunohistochemistry for GFAP and pSTAT3 was feasible in 68/85 (80%). Fifteen out of 68 patients (21.1%) had BM from luminal BC, 27/68 (39.7%) from HER2-positive BC, and 26/68 (39.2%) from TNBC. Fifty-six out of 68 (82.4%) showed positive staining of pSTAT3 in peritumoral RA, of which 9/68 (13.3%) scored with 3, 26/68 (38.2%) with 2, and 21/68 (30.9%%) with 1, while pSTAT3 expression was negative (score 0) in 12/68 (17.6%). High pSTAT3 expression (score 2-3) was observed in 17/27 (62.9%) BM from HER2-positive BC and in 15/26 (57.7%) BM from TNBC, while most of BM from luminal BC (12/15 - 80%) had low or absent pSTAT3 (score 0-1) (p=0.021). Overall i-PFS was 16 months (range 7-41): low pSTAT3 BM (score 0-1) had a median i-PFS of 21 months versus 12 months for high pSTAT3 BM (score 2-3). A shorter median i-PFS was observed in high pSTAT3 BM from TNBC (4 months) as compared with low pSTAT3 BM (11 months). Conversely, i-PFS of high pSTAT3 BM (7 months) was similar to low pSTAT3 BM (6 months) in HER2-positive BC. Conclusion pSTAT3 expression in RA of peritumoral tissue of BM from TNBC and HER2-positive BC is higher than in BM from luminal BC. Of note, patients with high pSTAT3 BM from TNBC progressed earlier in comparison with those with low pSTAT3, suggesting that pSTAT3 expression has an influence on the outcome.
P11.69.B <i>IDH1/2</i>wildtype gliomas grade 2 and 3 with molecular glioblastoma-like profile have a distinct course of epilepsy compared to<i>IDH1/2</i>wildtype glioblastomas
Authors: M P van Opijnen, C M S Tesileanu, L Dirven, P B van der Meer, M M J Wijnenga, A J P E Vincent, M L D Broekman, H J Dubbink, J M Kros, S G van Duinen, M Smits, P J French, M J van den Bent, M J B Taphoorn, J A F Koekkoek
Journal: Neuro-Oncology (2022)

Abstract Background IDH1/2 wildtype (IDHwt) glioma WHO grade 2 and 3 patients with pTERT mutation and/or EGFR amplification and/or +7/−10 chromosome gain/loss have a similar overall survival time as IDHwt glioblastoma patients, and are both considered glioblastoma IDHwt according to the WHO 2021 classification. However, differences in seizure onset have been observed. This study aimed to compare the course of epilepsy in the two glioblastoma subtypes. Material and Methods We analyzed epilepsy data of an existing cohort including IDHwt histologically lower-grade glioma WHO grade 2 and 3 with molecular glioblastoma-like profile (IDHwt hLGG) and IDHwt glioblastoma patients. Primary outcome was the incidence proportion of epilepsy during the disease course. Major secondary outcomes included onset of epilepsy, number of seizure days and antiepileptic drug (AED) polytherapy. Results Out of 254 patients, 78% (50/64) IDHwt hLGG and 68% (129/190) IDHwt glioblastoma patients developed epilepsy during the disease course (p=0.121). Epilepsy onset before histopathological diagnosis occurred more frequently in IDHwt hLGG compared to IDHwt glioblastoma patients (90% versus 60%, p&amp;lt;0.001), with a significantly longer median time to diagnosis (3.5 versus 1.3 months, p&amp;lt;0.001). Median total seizure days was also longer for IDHwt hLGG patients (7.0 versus 3.0, p=0.005), and they received more often AED polytherapy (32% versus 17%, p=0.028). Conclusion Although the incidence proportion of epilepsy during the entire disease course is similar, IDHwt hLGG patients show a significantly higher incidence of epilepsy before diagnosis and a significantly longer median time between first seizure and diagnosis compared to IDHwt glioblastoma patients, indicating a distinct clinical course.